GEMCITABINE
Clinical safety rating: avoid
Contraindicated (not allowed)
Gemcitabine is a nucleoside analog (2',2'-difluorodeoxycytidine) that is phosphorylated intracellularly to active diphosphate (dFdCDP) and triphosphate (dFdCTP) metabolites. dFdCDP inhibits ribonucleotide reductase, reducing deoxynucleotide pools for DNA synthesis. dFdCTP competes with deoxycytidine triphosphate for incorporation into DNA, causing masked chain termination and inhibiting DNA polymerase and repair.
| Metabolism | Gemcitabine is extensively metabolized intracellularly by deoxycytidine kinase (dCK) to monophosphate (dFdCMP), then by other kinases to active di- and triphosphates. Inactivated by cytidine deaminase (CDA) to 2',2'-difluorodeoxyuridine (dFdU), which is renally excreted. |
| Excretion | Primarily renal: ~92-98% of the dose excreted in urine, with <10% as unchanged gemcitabine and the majority as the inactive metabolite 2',2'-difluorodeoxyuridine (dFdU). Fecal excretion is minimal (<1%). |
| Half-life | Terminal elimination half-life for gemcitabine is 42-94 minutes (mean ~57 min) in plasma; for its metabolite dFdU, the half-life is 14-74 hours (mean ~40 h), which accumulates with repeated dosing and may contribute to prolonged systemic exposure. |
| Protein binding | Negligible; gemcitabine is <10% bound to plasma proteins. dFdU is also minimally bound. |
| Volume of Distribution | Volume of distribution for gemcitabine is 0.5-0.8 L/kg (approximately 50 L for a 70 kg adult), indicating distribution into total body water. For dFdU, Vd is about 0.15-0.2 L/kg, suggesting limited tissue penetration. |
| Bioavailability | Intravenous only (100% bioavailability). Oral bioavailability is <5% due to extensive first-pass metabolism, and not clinically used. |
| Onset of Action | Intravenous administration: Onset of antitumor effect is not immediate; clinical response typically observed after several weeks of therapy. For radiosensitization, effect occurs within hours of infusion. |
| Duration of Action | Duration of antitumor effect is variable and schedule-dependent; the drug is typically administered weekly for 3 weeks followed by a 1-week rest. Myelosuppression may last 7-14 days after infusion. |
1000-1250 mg/m² intravenously over 30 minutes on days 1 and 8 of a 21-day cycle.
| Dosage form | INJECTABLE |
| Renal impairment | For CrCl 30-80 mL/min: no adjustment; for CrCl <30 mL/min: use with caution at reduced dose; for CrCl <10 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: not recommended. |
| Pediatric use | Not established; safety and efficacy not determined. |
| Geriatric use | No specific dose adjustment; monitor renal function and hematologic toxicity closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and hemolytic uremic syndrome.
| Breastfeeding | Not recommended. High molecular weight but potential for excretion into breast milk; M/P ratio unknown. Infants at risk of severe adverse effects (myelosuppression, gastrointestinal toxicity). Discontinue breastfeeding during therapy and for at least 3 months after last dose. |
| Teratogenic Risk | Pregnancy category D. First trimester: Potential for teratogenicity (malformations, embryotoxicity) based on animal studies and its mechanism of action (antimetabolite). Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and neonatal myelosuppression. Avoid use unless maternal benefit outweighs fetal risk. |
■ FDA Black Box Warning
Gemcitabine can cause serious and sometimes fatal adverse effects including: hemolytic uremic syndrome (HUS), capillary leak syndrome (CLS), posterior reversible encephalopathy syndrome (PRES), pulmonary toxicity (pneumonitis, pulmonary edema), and severe myelosuppression (neutropenia, thrombocytopenia).
| Common Effects | other cancers |
| Serious Effects |
["Hypersensitivity to gemcitabine or any component of the formulation.","Severe myelosuppression (absolute neutrophil count < 500/mm³ and/or platelet count < 50,000/mm³) at start of cycle.","Concurrent radiation therapy (based on increased toxicity)"]
| Precautions | ["Myelosuppression (neutropenia, thrombocytopenia, anemia): Monitor blood counts.","Pulmonary toxicity (interstitial pneumonitis, pulmonary edema, ARDS): Discontinue if severe.","Hemolytic uremic syndrome (HUS): Discontinue if microangiopathic hemolytic anemia, thrombocytopenia, renal failure.","Capillary leak syndrome (CLS): Monitor for edema, hypotension, hemoconcentration.","Posterior reversible encephalopathy syndrome (PRES): Monitor for hypertension, seizures, headache, visual disturbances.","Hepatotoxicity: Monitor liver function.","Renal toxicity: Monitor renal function.","Fetal harm: Advise pregnant women of risk.","Radiation toxicity: Increased toxicity when given with radiation therapy."] |
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| Fetal Monitoring | Maternal: Complete blood count with differential (baseline and before each dose), hepatic (ALT, AST, bilirubin), and renal function (serum creatinine). Fetal: Ultrasound for growth, amniotic fluid volume, and morphology if exposed in second/third trimester; serial growth scans if continued use. |
| Fertility Effects | May cause irreversible gonadal suppression in both sexes. In males, oligospermia or azoospermia; in females, amenorrhea, ovarian failure, and reduced fertility potential. Pre-treatment fertility preservation counseling advised. |